This Program Project will develop a novel set of integrated nucleic acid hybridization technologies: oligonucleotide, surface and dye chemistry, fluidic methods for high speed microarry fabrication, a new microarry format for hybridization analysis and, finally, a novel high speed CCD based detection platform. The work is an extension of technology development which was funded by the Department of Commerce ATP program and which has already generated numerous publications and patents in the "biochip" area. The goal here is to greatly extend this biochip technology base for genetic analysis of lung tumors in a clinical context. The work is driven by two biological principles. The first is that, to be useful in the clinic, the hybridization technology must be very fast and sensitive, but relatively inexpensive, and simple enough to ensure rigorous QC and easy integration into available high throughput sample handling robotics. The second principle which drives the work is that the order to truly revolutionize cancer diagnosis, the technology must be capable of obtaining several different types of genetic information per day, on the same sample, in parallel fashion. In accord with those principles, we propose a technology platform which can process several hundred samples per day per workstation, and will generate heterogeneous data sets on each tumor of the following scale: point mutation (up to 3 genes), LOH (up to 10 loci), quantitation of gene expression at the MRNA level (as many as 100 genes per sample). To achieve those integrated technology goals, we have assembled a team with a record of innovation in nucleic acid and surface chemistry (Project 1), supercomputer modeling of nucleic acid and surface interactions (Project 2), innovative optical detector and microfluidics engineering (Project 3), workstation integration (Core A), cancer molecular biology, tumor pathology and tissue archive administration (Core B) and multidisciplinary research coordination (Core C).